Hypoxic vasospasm and/or thrombosis of the major coronary arteries may be instrumental in the development of both transient myocardial ischemia and fatal infarction. Recent evidence further indicates that the vascular endothelium may be an important modulator of coronary artery reactivity. Although many factors have been postulated to contribute to coronary vasospasm, relatively little is known about 1) their relative importance; 2) the appropriate vasoconstrictor stimuli and their origins; and 3) the mechanism by which coronary vasospasm is initiated. Furthermore, it is unclear to what extent coronary vasospasm can be induced by thrombus formation and/or the metabolic products of the thrombus. Conversely, it is not known whether coronary vasospasm could induce thrombus formation in the coronary arteries. This proposal will specifically address these important questions; our overall goal is to investigate in a collaborative effort, the interrelationships between hypoxic coronary vasospasm and thrombosis with emphasis on the role that the endothelial cell plays in modulating these events. In initial experiments, we have found that bovine aortic endothelial cells in culture synthesize and secrete a polypeptide which produces a sustained contraction of the isolated bovine, porcine or canine coronary artery. Also, it is now evident that hypoxic vasoconstriction in canine coronary arteries is dependent on the presence of an intact endothelial layer. The contraction may be mediated by a polypeptide secreted by the endothelial cells, for inhibitors to all of the major coronary agonist-receptor systems and to arachidonate metabolism did not affect the response to hypoxia. In addition, we have found that endothelial cells cultured in a hypoxic or acidotic environment secrete significantly less of the fibrinolytic activator protein - a condition which could favor thrombosis. These new findings and others dealing with mechanisms of hypoxic vasoconstriction, form the basis of our proposal. These findings are significant in that they provide a potentially important role for endothelial cell secretions in modulating thrombosis and coronary artery reactivity and/or responsiveness to hypoxic vasoconstriction. The proposed experiments with coronary vascular smooth muscle will utilize isolated rings derived from different segments of the major bovine and porcine epicardial arteries. Selected parameters of bovine endothelial cell function will be studied using primary cultures of aortic, coronary or left ventricular endothelial cells. This collaborative effort from two laboratories within the same department is likely to provide new and meaningful information which is relevant to our understanding and treatment of coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031543-02
Application #
3342750
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Hubel, C A; Highsmith, R F (1995) Endothelin-induced changes in intracellular pH and Ca2+ in coronary smooth muscle: role of Na(+)-H+ exchange. Biochem J 310 ( Pt 3):1013-20
Heffernan, M; Chance, A; Hess, E V et al. (1994) Alterations in human endothelial cell morphology, proliferation and function by a macrophage-derived factor. Ir J Med Sci 163:359-65
Highsmith, R F; Blackburn, K; Schmidt, D J (1992) Endothelin and calcium dynamics in vascular smooth muscle. Annu Rev Physiol 54:257-77
Sawaya, R; Highsmith, R F (1992) Postoperative venous thromboembolism and brain tumors: Part III. Biochemical profile. J Neurooncol 14:113-8
Blackburn, K; Highsmith, R F (1990) Nickel inhibits endothelin-induced contractions of vascular smooth muscle. Am J Physiol 258:C1025-30
Rapoport, R M; Stauderman, K A; Highsmith, R F (1990) Effects of EDCF and endothelin on phosphatidylinositol hydrolysis and contraction in rat aorta. Am J Physiol 258:C122-31
Highsmith, R F; Pang, D C; Rapoport, R M (1989) Endothelial cell-derived vasoconstrictors: mechanisms of action in vascular smooth muscle. J Cardiovasc Pharmacol 13 Suppl 5:S36-44;discussion S45
Whitmer, K R; Williams-Lawson, J S; Highsmith, R F et al. (1988) Effect of calcium channel modulators on isolated endothelial cells. Biochem Biophys Res Commun 154:591-605
Neely, A N; Nathan, P; Highsmith, R F (1988) Plasma proteolytic activity following burns. J Trauma 28:362-7
FitzGerald, O M; Hess, E V; Chance, A et al. (1987) Quantitative studies of human monokine-induced endothelial cell elongation. J Leukoc Biol 41:421-8

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